Combretastatin A-4 Analogs as Anticancer Agents

Chaudhary, Anurag; Pandeya, S. N.; Kumar, Praveen; Sharma, Pooja; Gupta, Shilpi; Soni, Nirupama B.; Verma, Kartikey; Bhardwaj, Gaurav

doi:10.2174/138955707782795647

Cited by 152 publications

(87 citation statements)

References 92 publications

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“…4) are of increasing therapeutic interest, but CA-4 seems to be more potent as a depolymerizing agent. Its anti-mitotic and cytotoxic properties have been reviewed by several authors [3,34,35]. Moreover, CA-4 shows a strong anti-angiogenic activity related to selective inhibition of the formation of new blood vessels in the cancer tissue [36,37].…”

Section: Stilbene Derivatives As Tubulin-interactive Agentsmentioning

confidence: 99%

“…CA-4 is one of the best-known inhibitors of tubulin polymerization in vitro. CA-4 binds to tubulin at the colchicine-binding site, leading to the formation of abnormal mitotic spindles as a result of the disturbance of the dynamic equilibrium of microtubule formation [35]. The IC 50 value (concentration that inhibits tubulin polymerization to 50%) of CA-4 was determined in several laboratories and ranged from 0.53 to 2.4 M [33,[38][39][40].…”

Section: Stilbene Derivatives As Tubulin-interactive Agentsmentioning

confidence: 99%

“…The IC 50 value (concentration that inhibits tubulin polymerization to 50%) of CA-4 was determined in several laboratories and ranged from 0.53 to 2.4 M [33,[38][39][40]. CA-4 exerts a potent cytotoxicity against many human cancer cell lines, including multi-drug resistant (MDR) cancer cells [35]. However, CA-4 does not display the expected activity in vivo due to its poor bioavailability caused by its low solubility and the instability of its cis conformation, which easily changes to form the trans-isomer [41].…”

Section: Stilbene Derivatives As Tubulin-interactive Agentsmentioning

confidence: 99%

“…Here, we survey the studies of novel classes of anti-mitotic agents based on combretastatin A-4 as the lead, focusing on compounds with a two-atom linker. Recently, numerous structural modifications of CA-4 have been made leading to the identification of groups and positions that are important from the point of view of its anti-tumor activity [35,60,61,62]. In general, these are modifications to the A ring, B ring and/or the double bond of CA-4.…”

Section: Other Synthetic Stilbene Derivatives As Tubulin-interactive mentioning

confidence: 99%

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Tubulin-interactive stilbene derivatives as anticancer agents

Mikstacka

Stefański

Różański

2013

Cellular and Molecular Biology Letters

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Microtubules are dynamic polymers that occur in eukaryotic cells and play important roles in cell division, motility, transport and signaling. They form during the process of polymerization of α- and β-tubulin dimers. Tubulin is a significant and heavily researched molecular target for anticancer drugs. Combretastatins are natural cis-stilbenes that exhibit cytotoxic properties in cultured cancer cells in vitro. Combretastatin A-4 (3′-hydroxy-3,4,4′, 5-tetramethoxy-cis-stilbene; CA-4) is a potent cytotoxic cis-stilbene that binds to β-tubulin at the colchicine-binding site and inhibits tubulin polymerization. The prodrug CA-4 phosphate is currently in clinical trials as a chemotherapeutic agent for cancer treatment. Numerous series of stilbene analogs have been studied in search of potent cytotoxic agents with the requisite tubulin-interactive properties. Microtubule-interfering agents include numerous CA-4 and transresveratrol analogs and other synthetic stilbene derivatives. Importantly, these agents are active in both tumor cells and immature endothelial cells of tumor blood vessels, where they inhibit the process of angiogenesis. Recently, computer-aided virtual screening was used to select potent tubulin-interactive compounds. This review covers the role of stilbene derivatives as a class of antitumor agents that act by targeting microtubule assembly dynamics. Additionally, we present the results of molecular modeling of their binding to specific sites on the α- and β-tubulin heterodimer. This has enabled the elucidation of the mechanism of stilbene cytotoxicity and is useful in the design of novel agents with improved anti-mitotic activity. Tubulin-interactive agents are believed to have the potential to play a significant role in the fight against cancer.

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Section: Stilbene Derivatives As Tubulin-interactive Agentsmentioning

confidence: 99%

Section: Stilbene Derivatives As Tubulin-interactive Agentsmentioning

confidence: 99%

Section: Stilbene Derivatives As Tubulin-interactive Agentsmentioning

confidence: 99%

Section: Other Synthetic Stilbene Derivatives As Tubulin-interactive mentioning

confidence: 99%

See 2 more Smart Citations

Tubulin-interactive stilbene derivatives as anticancer agents

Mikstacka

Stefański

Różański

2013

Cellular and Molecular Biology Letters

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“…Thus, most modifications of combretastatins have been directed to ring B and the ethenyl bridge. Modifications of ring B have included, but have not been limited to, different substitutions on the phenyl, heteroaromatic or heterocyclic rings [21]- [24], and the unstable ethenyl bridge is substituted either with sulfonate ( Figure 1) [25] [26], chalcone [27] [28], imidazole [29], triazole [30] [31], furazan [32], pyrazole or 1,3-thiazole [33] derivatives.…”

Section: Introductionmentioning

confidence: 99%

Novel Cytocidal Substituted Phenyl 4-(2-Oxoimidazolidin-1-yl) Benzenesulfonates and Benzenesulfonamides with Affinity to the Colchicine-Binding Site: Is the Phenyl 2-Imidazolidinone Moiety a New Haptophore for the Design of New Antimitotics?

Fortin¹,

Wei²,

Kotra³

et al. 2015

OJMC

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Phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs) and phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonamides (PIB-SAs) are new, potent combretastatin A-4 (CA-4) analogs designed on the basis of their common phenyl 2-imidazolidone moiety. This phenyl 2-imidazolidone group is a bioisosteric equivalent of the trimethoxyphenyl group also found in colchicine, podophyllotoxin and several other ligands of the colchicine-binding site (C-BS). In this study, we investigate the interactions involved in the binding of PIB-SO and PIB-SA into the C-BS. We describe three distinct pockets (I, II, and III) as key structural elements involved in the interactions between the * Corresponding author. S. Fortin et al. 10C-BS and PIB-SOs as well as PIB-SAs. We show that PIB-SOs and PIB-SAs adopt 4 and 3 distinct binding conformations, respectively, within the C-BS. The binding conformations I and IV are common to most PIB-SOs and PIB-SAs exhibiting high affinity for the C-BS and high cytocidal potency. In addition, binding conformation I is the main conformation adopted by PIB-SOs, PIB-SAs, T138067, ABT-751, colchicine and CA-4. We also observe that the sulfonate and the sulfonamide moieties of PIB-SOs and PIB-SAs are bioisosteric equivalents. Interestingly, we further find that a large portion of the phenyl 2-imidazolidinone moiety in these analogs does not bind to pocket I unlike the trimethoxyphenyl moiety found in several antimicrotubule agents such as colchicine, CA-4 and podophyllotoxin, suggesting that the phenyl 2-imidazolidinone group may represent a new haptophoric moiety useful for the design of new C-BS inhibitors mimicking the tropolone and the methoxylated phenolic moieties of colchicine and CA-4, respectively.

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Bioactive Stilbenes

2009

Stilbenes

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Combretastatin A-4 Analogs as Anticancer Agents

Cited by 152 publications

References 92 publications

Tubulin-interactive stilbene derivatives as anticancer agents

Tubulin-interactive stilbene derivatives as anticancer agents

Novel Cytocidal Substituted Phenyl 4-(2-Oxoimidazolidin-1-yl) Benzenesulfonates and Benzenesulfonamides with Affinity to the Colchicine-Binding Site: Is the Phenyl 2-Imidazolidinone Moiety a New Haptophore for the Design of New Antimitotics?

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